Biomedical subjects

T H Moran

Publications and source records attributed to T H Moran.

At least 37 records · Page 2Linked to original sources

PubMed2000

Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.

Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.

Amphetamine↗

PubMed2000

Curt Richter and regulatory physiology.

Curt Richter made seminal contributions to our understanding of a number of issues regarding the relationships between physiology and behavior. He was the first to conceptualize behavior as an aspect of regulatory physiology. These ideas developed from his work on behavioral responses to a variety of physiological perturbations. The classic example is Richter's demonstration of the development of avid sodium ingestion in response to urinary sodium loss after adrenalectomy. Some of Richter's ideas on the nature and underlying physiology of specific appetites maintain their influence and continue to stimulate active investigation. Others, focused on abilities to self-select balanced diets, have not borne the test of time or experimental challenge. As current research takes a more molecular focus, Richter's ideas on behavior in the service of the internal milieu maintain their currency, and the search for the molecular bases for these relationships should serve as a research focus.

History, 20th Century↗

PubMed1999

Inhibition of gastric emptying by bombesin-like peptides is dependent upon cholecystokinin-A receptor activation.

The amphibian peptide bombesin (BN) and the related mammalian peptides gastrin-releasing peptide (GRP) and neuromedin B (NMB) inhibit gastric emptying in rats. Exogenous administration of BN stimulates the release of cholecystokinin (CCK), a gastrointestinal peptide that also potently inhibits gastric emptying. To determine whether the inhibition of gastric emptying by BN-like peptides is mediated by a CCK-dependent mechanism, we examined the ability of the CCK-A receptor antagonist, devazepide, to block the inhibition of saline gastric emptying produced by BN, GRP18-27 and NMB. Using the same dosages as in the gastric emptying experiment, we also evaluated the effect of devazepide on feeding suppression produced by systemically administered BN. Our results showed that devazepide completely blocked the suppression of gastric emptying produced by BN, GRP18-27 and NMB but had no effect on BN-induced suppression of food intake. These results suggest that BN-like peptides inhibit gastric emptying through an indirect mechanism that is dependent upon CCK-A receptor activation. In contrast, the suppression of food intake by BN, in this experimental paradigm, is independent of CCK-A receptors.

Animals↗

PubMed1999

Viral teratogenesis: brain developmental damage associated with maturation state at time of infection.

The rat brain continues to mature after birth and is particularly vulnerable to developmental damage following perinatal insult. Borna disease virus (BDV) infection of postnatal day one (PND-1) rat brain causes a non-encephalitic, persistent infection associated with developmental neuroanatomical and behavioral abnormalities. To test the hypothesis that BDV infection during different brain developmental stages yields variable pathological and clinical disease sequelae, rats were examined for BDV-induced neuroanatomical and behavioral abnormalities following inoculation with BDV on PND-15, and the findings were compared to those resulting from inoculation on PND-1. Similar to rats inoculated with BDV on PND-1, PND-15 inoculated rats developed a persistent infection associated with body weight stunting, abnormal salt taste preference and hippocampal neuron degeneration. However, unlike rats infected with BDV on PND-1, PND-15 inoculated rats did not show signs of cerebellar hypoplasia or hyperactivity. Thus, the risk of BDV-induced damage to specific brain regions, and their associated behaviors, appears, in part, dependent upon the brain's developmental stage at time of BDV-infection. These studies provide evidence of the selective vulnerability of specific neuroanatomic regions and behaviors in developing nervous system to virus-induced damage.

Aging↗

PubMed1999

Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits.

In neonatally inoculated rats, Borna disease virus (BDV) leads to a persistent infection of the brain in the absence of an inflammatory response and is associated with neuroanatomic, developmental, physiologic, and behavioral abnormalities. One of the most dramatic sites of BDV-associated damage in the neonatal rat brain is the dentate gyrus, a neuroanatomic region believed to play a major role in spatial learning and memory. The absence of a generalized inflammatory response to neonatal BDV infection permits direct effects of viral damage to the dentate gyrus to be examined. In this report, neonatally BDV-infected rats at various stages of dentate gyrus degeneration were evaluated in the Morris water maze, a swimming test that assesses the rats' capacity to navigate by visual cues. Our data demonstrate progressive spatial learning and memory deficits in BDV-infected rats that coincided with a gradual decline in the estimated hippocampal dentate gyrus neuron density.

Animals↗

PubMed1999

Persistent neonatal Borna disease virus (BDV) infection of the brain causes chronic emotional abnormalities in adult rats.

Neonatal Borna disease virus (BDV) brain infection results in selective developmental damage to the hippocampal dentate gyrus and the cerebellum. When mature, neonatally BDV-infected rats show extreme locomotor hyperactivity and reduced freezing behavior in novel environments. Traditional interpretation of both of these behavioral abnormalities would suggest decreased anxiety in infected rats compared to normal animals. However, it also possible that the locomotor hyperactivity in infected rats reflects higher rather than reduced anxiety, and is the result of increased escape responses to aversive stimuli. The present experiments were undertaken to test a hypothesis about elevated anxiety in neonatally BDV-infected adult Lewis rats by studying their species-specific fear-related responses. Compared to normal subjects, BDV-infected rats exhibited locomotor hyperactivity and elevated defecation in a highly aversive, brightly lit open field. As expected, in a less aversive, dimly lit open field, uninfected controls increased ambulation, whereas infected rats significantly decreased locomotor activity and defecation. Unlike uninfected rats, BDV-infected rats exhibited an attenuated freezing response immediately after loud auditory stimuli. On the contrary, immediate freezing responses following footshock were comparable in the two groups of animals indicating an intact ability to freeze in BDV-infected rats. Despite a decreased baseline startle responsiveness, BDV-infected rats demonstrated increased sensitization of the startle response by preceding footshocks, suggesting a tendency toward elevated escape responses. Compared to normal subjects, BDV-infected rats showed decreased conditional freezing and elevated conditional defecation response in the context previously paired with aversive stimulation indicating sparing of an autonomic component of fear conditioning. The findings indicate that neonatally BDV-infected adult rats are hyperreactive to aversive stimuli, possibly as a result of chronic emotional abnormalities.

Affective Symptoms↗

PubMed1999

Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism.

Play behavior, nonsocial exploratory activity, and nonplay social interaction were observed in male juvenile Lewis rats with brain developmental injury following neonatal infection with Borna disease virus (BDV). These behaviors were tested using the 'intruder-resident' paradigm, with social isolation of residents for six days prior to testing. Four experimental pairings of infected (BDV) and uninfected (NL) rats were studied as follows: NL-NL; NL BDV; BDV NL; and BDV-BDV (the first member is the resident, the second member is the intruder). Observation of social activities was carried out for 10 min on two consecutive days. Nonsocial exploratory activity (e.g. ambulation and rearing) was similar in BDV and NL residents. Duration of nonplay social investigation (e.g. sniffing, approach, and follow) was higher in BDV residents as compared to NL residents when tested on the first test day. On the second day, all rats showed similar level of nonplay social interaction. When confronted with NL intruders, NL residents exhibited significantly more play behavior compared to the NL-BDV, BDV NL and BDV-BDV pairs, when play behavior was measured by the number of 'pins'. Moreover, irrespective of a type of intruder, NL residents demonstrated higher play soliciting behavior than BDV residents, indicating attenuated readiness to play in BDV-infected rats. The number of pins and play solicitations in BDV-NL pairs significantly increased over the two days of testing, while play activity in NL-BDV pairs declined on the second test day. This pattern suggests that the degree of social reinforcement on the first day of testing affected the level of play on the second day. These data demonstrate deficits in play behavior and other social interactions following BDV-associated developmental brain injury, thus supporting the value of the neonatally BDV-infected rat as an animal model of autism.

Animals↗

PubMed1999

Interactions between gastric volume and duodenal nutrients in the control of liquid gastric emptying.

We examined the relationships between gastric volume and duodenal glucose load in the regulation of gastric emptying in adult male rhesus monkeys. Intragastric glucose loads (0.125 g/ml) of volumes ranging from 150 to 375 ml empty from the stomach at the same rate from 20 to 120 min. However, to achieve these equivalent emptying rates, progressively larger volumes were emptied in the initial 20 min with increasing gastric volume. Duodenal glucose infusions dose dependently inhibited the 10-min emptying of various volumes of intragastric saline. Although increasing gastric volume resulted in increased emptying, duodenal glucose right-shifted the relationship between initial gastric volume and volume emptied. These data demonstrate that liquid nutrient gastric emptying represents an interaction between gastric volume and nutrient-induced duodenal feedback. For controlled duodenal caloric delivery rates to be established, sufficient nutrient emptying must occur to increase the magnitude of duodenal feedback to withhold a given gastric volume.

Animals↗

PubMed1999

Meal-synchronized CEA in rats: effects of meal size, intragastric feeding, and subdiaphragmatic vagotomy.

Within a feeding schedule of intermittent food access, large meals have the ability to induce activity at the same time the next day [circadian ensuing activity (CEA)]. In these experiments, we evaluated the minimum meal size necessary to induce CEA and whether oral-pharyngeal factors and afferent vagal activity played necessary roles in the induction of the underlying process. In experiment 1, every 33 h rats were given two meals separated by a 2-h interval. The size of the first meal was varied, while total intake every feeding cycle was held constant. When the initial meal was <10 g (34 kcal) CEA occurred later, indicating that such a meal size was subthreshold for inducing CEA. In experiment 2, rats were given intragastric (IG) meals every 33 h, before and after complete subdiaphragmatic vagotomy. IG nutrient meals induced CEA, indicating that extensive oral-pharyngeal experience was not necessary for CEA induction. CEA occurred in vagotomized rats but, compared with intact rats, appeared to occur later relative to nutrient infusion, indicating that afferent vagal activity may be sufficient but not necessary to induce CEA.

Animals↗

PubMed1999

Central leptin modulates behavioral and neural responsivity to CCK.

The mechanisms through which leptin, the protein product of the ob gene, affects food intake remain to be determined. To assess whether the actions of leptin depend on modulation of within-meal satiety signals, we measured the effect of third ventricular leptin administration on the satiety actions of CCK. Leptin (10 micrograms) administered 1 h before 30-min access to a liquid diet had no effect on intake when administered alone, but doses of 3.5 or 10 micrograms dose dependently increased the suppression of intake produced by 1 nmol/kg CCK. Examination of patterns of c-Fos activation induced by 3.5 micrograms leptin and 1 nmol/kg CCK revealed that the combination produced significant c-Fos activation within the area postrema and the caudal and medial nucleus of the solitary tract (NST) compared with either leptin or CCK treatments alone. The leptin-CCK combination also resulted in increased c-Fos activation within the paraventricular nucleus of the hypothalamus above that produced by leptin alone. These data suggest that the actions of leptin in food intake are mediated through its ability to modulate responsivity to within-meal satiety signals.

Animals↗

PubMed1999

Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression.

Subdiaphragmatic vagal afferent (SVA) signals arising from gut sites may provide critical feedback for the control of food intake within a meal. To evaluate the role of SVAs in both spontaneous and scheduled meals, food intake was assessed in two paradigms in male Sprague-Dawley rats. In the first study, control (Con) rats (n = 6) and rats with subdiaphragmatic vagal deafferentation (SDA) (n = 7) had 12-h nightly access to Ensure liquid diet (1 kcal/ml). SDA rats had larger and fewer meals and maintained initial rapid rates of licking, yet total numbers of licks were unaffected. In the second study, Con (n = 8) and SDA (n = 7) rats had scheduled access to 12. 5% liquid glucose after overnight food deprivation. Glucose intake was assessed after 5-ml gastric preloads of 0.9% saline or glucose, peptone, and Intralipid solutions at three concentrations (0.5, 1, and 2 kcal/ml). Glucose and peptone preloads suppressed intake similarly in Con and SDA rats, whereas Intralipid was ineffective. These results suggest that meal-related SVA signals 1) are not critical in determining preload-induced feeding suppression after deprivation, yet 2) contribute to satiety during spontaneous meals.

Administration, Oral↗

PubMed1999

Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors.

Adult Otsuka Long-Evans Tokushima fatty (OLETF) rats lack functional cholecystokinin A (CCK-A) receptors, are diabetic, hyperphagic, and obese, and have patterns of ingestion consistent with a satiety deficit secondary to CCK insensitivity. Because dietary fat potently stimulates CCK release, we examined how dietary fat modulates feeding in adult male OLETF rats and their lean [Long-Evans Tokushima (LETO)] controls. High-fat feeding produced sustained overconsumption of high-fat diet (30% corn oil in powdered chow) over a 3-wk period in OLETF but not LETO rats. We then assessed the ability of gastric gavage (5 ml, 1-2 kcal/ml x 15 s) or duodenal preloads (1 kcal/ml, 0.44 ml/min x 10 min) of liquid carbohydrate (glucose), protein (peptone), or fat (Intralipid) to suppress subsequent 30-min 12.5% glucose intake in both strains. In OLETF rats, gastric and duodenal fat preloads were significantly less effective in suppressing subsequent intake than were equicaloric peptone or glucose. These results demonstrate that OLETF rats fail to compensate for fat calories and suggest that their hyperphagia and obesity may stem from a reduced ability to process nutrient-elicited gastrointestinal satiety signals.

Animals↗

PubMed1999

Gastric and duodenal features of meals mediate controls of liquid gastric emptying during fill in rhesus monkeys.

To study the dynamics of liquid gastric emptying in rhesus monkeys under conditions that simulated gastric fill during a meal, we measured the gastric emptying of liquid glucose at various concentrations and volumes when administered intragastrically at rates ranging from 12.5 to 37.5 ml/min. Glucose gastric emptying was faster during than following the period of gastric fill. At a single glucose concentration, volume infused rather than the rate of filling determined the volume emptied. Lower glucose concentrations emptied more slowly than physiological saline. As glucose concentration increased, emptying during fill slowed. Duodenal glucose infusions greatly slowed the rate of saline emptying during fill, demonstrating duodenal feedback control. Although casein hydrolosate emptied more rapidly than glucose, the dynamics of volume and concentration dependency and the role of duodenal feedback were similar. These data reveal that both gastric volume and duodenal negative feedback controls important in gastric emptying following stomach filling also contribute to its control during fill.

Animals↗

PubMed1998

Load-sensitive rat gastric vagal afferents encode volume but not gastric nutrients.

To assess nutrient sensitivity in a population of gastric load-sensitive vagal afferents, their neurophysiological activity was examined in anesthetized rats with inflated pyloric cuffs after gastric infusion of a range of volumes of nutrient and equiosmotic saline solutions. Responses to physiological saline loads (1, 2, 4, and 8 ml) were compared with responses elicited by the same volume range of carbohydrate (12.5% glucose), protein (12.5% peptone), and equiosmotic hypertonic (750 mosM) saline. The threshold load volume of physiological saline required to increase gastric vagal afferent activity was 1 ml. Thereafter, there was a dose-dependent relationship between increasing gastric volume and firing rate and between gastric volume and pressure. The dose-response relationships elicited by glucose, peptone, and equiosmotic hypertonic saline loads did not differ from those elicited by physiological saline loads. These data identify a population of gastric load-sensitive vagal afferents unresponsive to the chemical composition of gastric contents and are consistent with a role for vagal gastric volume signals but not gastric nutrient content in the negative feedback control of ingestion.

Afferent Pathways↗

PubMed1998

Disordered food intake and obesity in rats lacking cholecystokinin A receptors.

Otsuka Long-Evans Tokushima Fatty (OLETF) rats develop obesity, hyperglycemia, and non-insulin-dependent diabetes mellitus and do not express cholecystokinin A (CCK-A) receptors, the receptor subtype mediating the satiety actions of CCK. In short-term feeding tests, male OLETF rats were completely resistant to exogenous CCK, and their response to bombesin was attenuated. Comparisons of liquid meal consumption in OLETF and control Long-Evans Tokushima (LETO) rats demonstrated that 1) OLETF rats had greater intakes during 30-min scheduled daytime meals and significantly larger and fewer spontaneous night-time meals and 2) although the initial rates of licking were the same, OLETF rats maintained the initial rate longer and the rate at which their licking declined was slower. In 24-h solid food access tests, OLETF rats consumed significantly more pellets than LETO controls, and this increase was attributable to significant increases in meal size. Together, these data are consistent with the interpretation that the lack of CCK-A receptors in OLETF rats results in a satiety deficit leading to increases in meal size, overall hyperphagia, and obesity.

Animals↗

PubMed1998

Duodenal nutrient exposure elicits nutrient-specific gut motility and vagal afferent signals in rat.

Volume and chemical characteristics of meals in the gut have been proposed to generate vagal afferent signals that mediate the negative feedback control of ingestion and gastric emptying. Furthermore, duodenal nutrients elicit changes in gastrointestinal motility that may stimulate mechanosensitive vagal afferents. The degree to which the activity of an individual vagal afferent fiber can be modified by moth mechanical and nutrient properties in the gut remains unclear. The present studies evaluated the relationships between distal antral and proximal duodenal load-sensitive vagal afferent activity and gastroduodenal motility in response to duodenal nutrient exposure in ketamine-xylazine-anesthetized rats. Duodenal carbohydrate (glucose) and amino acid (peptone) infusions (0.2 ml/min, 0.2-0.5 kcal/ml) stimulated concentration-dependent increases in 1) antroduodenal contractions and 2) antral and duodenal vagal afferent activity beyond those attributable to osmolarity alone. In addition, duodenal peptone was more effective than equicaloric glucose in eliciting this vagal activity. These data demonstrate that the proximal duodenum can discriminate its nutrient chemical contents and that gastroduodenal load-sensitive vagal afferents indirectly transduce nutrient chemical information.

Animals↗

PubMed1997

Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice.

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked. decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar changes in both strains of mice. In contrast to METH, MDMA caused greater percentage decreases in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) caused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood-brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH into the brain.

Animals↗

PubMed1997

Characterization of bombesin binding sites in the rat stomach.

We characterized the bombesin receptor population in the rat stomach and determined the receptor subtype mediating the contractile effect of bombesin in the gastric fundus. Using in vitro receptor autoradiography, we evaluated the ability of the specific gastrin-releasing peptide-preferring receptor antagonist [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester to inhibit binding of 125I-[Tyr4]bombesin to the gastric fundus, corpus and antrum. Binding to these regions was completely inhibited by [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester suggesting that these receptors are the gastrin-releasing peptide-preferring subtype. We found that the rank order of potency for the contractile effect of bombesin, and the related mammalian peptides neuromedin C and neuromedin B, was bombesin > neuromedin C > neuromedin B. [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester was equipotent in antagonizing contractions produced by all three peptides. Furthermore, receptor tachyphylaxis to either neuromedin C or neuromedin B abolished the subsequent contractile response elicited by neuromedin C and neuromedin B, suggesting that one bombesin receptor subtype mediates rat gastric fundal contractions. Together, these results demonstrate that the bombesin receptor subtype in the rat stomach is gastrin-releasing peptide-preferring subtype and that this subtype is responsible for the effects of bombesin-like peptides on fundal smooth muscle contraction.

Animals↗